Despite advances in antiviral therapy, control of infection with the human immunodeficiency virus (HIV) is not completely achieved in all patients. A majority of HIV-infected women receiving HAART present good virus control and recovery of CD4 counts upon treatment. However, about a third of those with good viral response and CD4 counts have a poor recovery of CD4 T cell function as evaluated by secretion of cytokines in memory responses to HIV and other common microorganisms. The reasons for this discrepancy in function are unclear but important to investigate because those patients with poor cytokine secretion, reflecting a defective CD4 T cell function, may be at increased risk of disease progression despite HAART. In addition, disease severity may accelerate in case of therapy failure or interruption. This observation also highlights the fact that recovery of CD4 counts in treated HIV infection does not always correlate with recovery of CD4 function. Current technology for DNA sequencing has allowed for mapping of single nucleotide polymorphisms (SNPs) in the human genome, which opens the possibility to investigate genetic factors influencing the pathogenesis of disease in humans. Applying a dual approach by investigating genetics factors and immune function, we are currently studying cytokine secretion (interferon-gamma and interleukin-10) and its association with nucleotide polymorphisms in the corresponding cytokine genes using the well-characterized cohort of women in the Women's Interagency HIV Study (WIHS). We propose to investigate the role that the suppressors of cytokine signaling (SOCS proteins), a novel protein family with potent modulatory effect on cytokine secretion, may have on T helper cell function in HIV-infected women. We aim to investigate levels of mRNA expression for SOCS1, SOCS2 and SOCS3, as well as nucleotide polymorphisms in the corresponding SOCS genes. The emerging results will provide evidence on whether SNPs in any of the SOCS1, SOCS2 and SOCS3 genes are associated with levels of secreted cytokines (data available from our current studies) and their role in immune recovery and disease progression following treatment of HIV infection. This novel approach will combine the expertise of molecular epidemiology with cellular immunology and will advance our current understanding of HIV infection and effect of treatment. We also expect that a better understanding of immune function in controlled HIV infection may lead to improved therapies. The success of the proposed study is greatly facilitated by the availability of extensive data and repository samples from the participating women in WIHS. The results will be used as preliminary data for a larger and more comprehensive study of cytokine function and genetic polymorphisms in WIHS women. PUBLIC HEALTH RELEVANCE: Although HAART is efficient in controlling viral load in HIV infection, about a third of treated women in the Women's Interagency HIV Study (WIHS) present low capacity for secretion of the antiviral factor interferon-gamma by memory CD4 T cells, indicating relative recovery of CD4 counts but poor recovery of function. Also, markers of cell inflammation are commonly observed in HIV infection. We propose here to study the role of genes coding for proteins that control interferon-gamma secretion as a reason for poor recovery of CD4 function in these women. We will also study the role of these genes on the level of cell inflammation. As the number of HIV-infected women increase, especially among African-American and Latino minorities, it is highly relevant to understand the reasons for disease progression despite efficient anti-viral treatment.